Process for preparing alkoxypyrazine derivatives

ABSTRACT

A process for preparing alkoxypyrazine derivatives of the general formula: ##STR1## These alkoxypyrazine derivatives are obtained by reacting a glyoxal derivative of the general formula: ##STR2## and an aminomidiate of the general formula: ##STR3## The alkoxypyrazine derivatives are important intermediates for preparing pharmaceutically active compounds.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a novel process for preparing alkoxypyrazinederivatives of the general formula: ##STR4## in which R¹ denoteshydrogen, alkyl or aryl, R² denotes hydrogen, alkyl, --CONH₂, --COOR⁴,in which R⁴ denotes alkyl, or --C(NH)OR⁴, in which R⁴ is as definedabove, and R³ denotes alkyl or aryl. Moreover, the invention relates toa novel process for preparing alkoxypyrazineamine derivatives of thegeneral formula: ##STR5## in which R¹ and R³ are as defined above.

2. Background Art

Both the alkoxypyrazine derivatives of the general formula Ia and thealkoxypyrazineamine derivatives of the general formula V are importantintermediates for preparing pharmaceutically active compounds[Katritzky, Comprehensive Het. Chem.,Vol. 3, (1984), 179-197].

A number of processes for preparing pyrazine derivatives are known fromthe above-mentioned literature reference.

British Published Patent Application No. 922,725, for example, describesa process for preparing 3-methoxy-5-methylpyrazine-2-amine by reactionof 3-chloro-5-methylpyrazine-2-amine with sodium methoxide.

BROAD DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a novel alternativeaccess to alkoxypyrazine and alkoxypyrazineamine derivatives. Thisobject is successfully achieved by the novel process according to theinvention.

The key step of the synthesis according to the invention according tothe first process of the invention is the reaction of a glyoxalderivative of the general formula: ##STR6## in which R¹ is as definedabove with an aminoimidate of the general formula: ##STR7## in which R²and R³, are as defined above to give the alkoxypyrazine derivative ofthe general formula: ##STR8## in which R¹ denotes hydrogen, alkyl oraryl, R² denotes hydrogen, alkyl, --CONH₂, --COOR⁴, in which R⁴ denotesalkyl, or --C(NH)OR⁴, in which R⁴ is as defined above, and R³ denotesalkyl or aryl.

The radicals R¹ to R⁵ are as defined below:

Alkyl denotes a C₁ -C₆ -alkyl group, specifically methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl and its isomers

Alkyl preferably denotes a C₁ -C₄ -alkyl group. The alkyl group canoptionally be substituted by one of the alkyl groups mentioned, by aryl,by a halogen, by an alkoxy group, by an amino, by an alkylamino or by adialkylamino group.

For the purpose of the invention, aryl is to be understood as anoptionally substituted phenyl or naphthyl group. Suitable substituentsare the above-mentioned alkyl groups, halogen, alkoxy, amino, alkylaminoor dialkylamino.

The preferred aryl group is phenyl. The preferred aryl-substituted alkylgroup is benzyl. For the purpose of the invention, halogen denotesfluorine, chlorine, bromine or iodine, preferably chlorine.

Depending on the substitution pattern of the reactants, the group R¹ canbe positioned regioselectively in position 5 or position 6 of thealkoxypyrazine derivative.

Generally and also preferably, an alkoxypyrazine derivative of thegeneral formula: ##STR9## results in which R¹ is in position 5.

The glyoxal derivatives of the general formula II are generallyavailable commercially. This is true in particular for the preferablyused compounds glyoxal (R¹ =H), methylglyoxal (R¹ =CH₃) andphenylglyoxal (R¹ =phenyl). However, it is also possible to employ otherglyoxal compounds of the general formula II where R¹ =t-butyl orhaloalkyl, such as, for example, di- or triflhalomethyl, in particulardi- or trifluoromethyl or di-trichloromethyl.

The aminoimidate of the general formula III used as reaction partner ofthe glyoxal derivative of the general formula II is a compound whosepresence can be reaffirmed unambiguously, but which can usually not beisolated in stable form. According to one subembodiment of theinvention, the aminoimidate of the general formula III is thereforadvantageously prepared by reacting an aminonitrile of the generalformula: ##STR10## in which R⁵ has the meaning of R² or of cyano, withan alkali metal alkoxide or alkaline earth metal alkoxide and thenreacted further, directly and without isolation, with the glyoxalderivative of the general formula II to give the alkoxypyrazinederivative of the general formula Ia.

The reaction is advantageously carried out by initially charging theamino nitrile of the general formula IV in a suitable solvent,preferably in an aliphatic alcohol, followed by reaction with the alkalimetal alkoxide or alkaline earth metal alkoxide in question at atemperature of advantageously -30° C. to 150° C.

Preference is given to using alkali metal alkoxides, such as sodiummethoxide or potassium methoxide or sodium ethoxide or potassiumethoxide.

Depending on the group R² in the resulting aminoimidate of the generalformula III, it may be advantageous to neutralize the reaction mixturewith a suitable acid beforehand.

Suitable acids are simple carboxylic acids, such as acetic acid, ormineral acids, such as, sulfuric acid or hydrochloric acid.

The aminoimidate of the general formula III usually can not be isolatedin stable form, but its presence can be reaffirmed unambiguously byspectroscopic methods such as ¹³ C NMR. Consequently, further reactionwith the glyoxal derivative usually follows. This is advantageouslycarried out at a temperature of -30° C. to 150° C., preferably of -10°C. to 10° C.

The glyoxal derivative of the general formula II is usually employed ina slight excess, based on the aminonitrile of the general formula IV.

The reaction has usually ended after 0.1 hour to 40 hours, and thealkoxypyrazine of the general formula I can then be isolated in acustomary manner, for example by extraction from the reaction mixture.

Alkoxypyrazine derivatives of the general formula Ia where R¹ and R³denote alkyl or aryl and R² denotes --CONH₂, COOR⁴, where R⁴ denotesalkyl, or --C(NH)OR⁴ , where R⁴ is as defined above, are novel and notknown from the literature and are therefore also part of thesubject-matter of the present invention. Specifically, such novelalkoxypyrazine derivatives are:

3-methoxy-5-methylpyrazine-2-carboxamide;

3-ethoxy-5-methylpyrazine-2-carboxamide;

methyl 3-methoxy-5-methylpyrazine-2-carboxylate;

methyl 3-ethoxy-5-methylpyrazine-2-carboxylate;

3-methoxy-5-phenylpyrazine-2-carboxamide;

3-ethoxy-5-phenylpyrazine-2-carboxamide;

methyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate;

methyl 3-ethoxy-5-methylpyrazine-2-imidocaroxylate;

ethyl 3-methoxy-5-methylpyrazine-2-carboxylate; and

ethyl 3-ethoxy-5-methylpyrazine-2-carboxylate.

The reaction according to the invention is preferably suitable forpreparing 3-methoxy-5-methylpyrazine-2-carboxamide (general formula Ibwhere R¹ denotes methyl, R² denotes --CONH₂, and R³ denotes methyl). Tothis end, either 2-amino-2-cyanoacetamide (general formula IV where R⁵denotes --CONH₂) or 2-aminomalononitrile (general formula IV where R⁵denotes --CN), or a salt thereof, can be used as the starting material.

Starting from 2-amino-2-cyanoacetamide, the target compound is obtainedby the above-described reaction with the alkali metal alkoxide oralkaline earth metal alkoxide and subsequent neutralization via theaminoimidate intermediate (general formula III where R² denotes --CONH₂and R³ denotes methyl) and after reaction with methylglyoxal (generalformula II where R¹ denotes methyl).

Starting from 2-aminomalononitrile, or a salt thereof, the targetcompound is obtained by the above-described reaction with the alkalimetal alkoxide or alkaline earth metal alkoxide and subsequentneutralization via the aminoimidate intermediate (general formula IIIwhere R² denotes --C(NH)OCH₃ and R³ denotes methyl), after its reactionwith methylglyoxal (general formula II where R¹ denotes methyl) viamethyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate, after itsacidification to give methyl 3-methoxy-5-methylpyrazine-2-carboxylateand finally after its amidation.

In the last variant, methyl3-methoxy-5-methylpyrazine-2-imidocarboxylate is not isolated butdirectly converted into the carboxylic ester mentioned by acidificationof the reaction mixture. The acidification and the amidation is carriedout in a known manner using a mineral acid and ammonia, respectively.

The alkoxypyrazine derivatives of the general formula Ia preparableaccording to the invention where R² denotes --CONH₂ and R¹ and R³ aredefined as above, can, according to a further aspect of the invention,be converted, according to the principles of the Hofmann degradation,into alkoxypyrazineamine derivatives of the general formula: ##STR11##where R¹ and R³ are as defined above, using an alkali metal hypohalite.

Preference is given to preparing, starting from the alkoxypyrazinederivatives of the general formula Ib, the alkoxypyrazineaminederivatives of the general formula: ##STR12## in which R¹ and R³ are asdefined above.

The Hofmann degradation is known from the literature. The reaction isusually carried out using an alkali metal hypobromite solution, which iscustomarily prepared from the corresponding alkali metal hydroxide andbromine, at a reaction temperature between -20° C. and 100°C.

The alkoxypyrazineamine derivative can be isolated from the reactionmixture in a customary manner known to the person skilled in the art,for example, by extraction.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1

(a) Synthesis of methyl (2-amino-2-carbonyl)acetoimidate

Under argon, 1.09 g (10.3 mmol) of 2-amino-2-cyanoacetamide wasinitially charged in 11 g of methanol. 0.29 g (1.6 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred at 20° C.for 2 hours. The structure of the title product was confirmed by NMR,with the data being:

¹ H-NMR (DMSO-d₆, 400 MHz)δ: 3.85 (s, 3H);

4.18 (s, 1H);

8.2-8.6 (sb, 1H).

¹³ C-NMR (DMSO-d₆, 400 MHz)δ: 52.27 (q);

55.83 (d);

171.66 (s);

172.78 (s).

(b) Synthesis of 3-methoxy-5-methylpyrazine-2-carboxamide

Under argon, 6 g (60.5 mmol) of 2-amino-2-cyanoacetamide was initiallycharged in 67 g of methanol. 1.67 g (9.3 mmol) of sodium methoxidesolution (30%) was added and the mixture was stirred for at 20° C. 2hours. After neutralization with 0.558 g (9.3 mmol) of acetic acid,11.55 g (64.1 mmol) of methylglyoxal solution (40%) was added. Themixture was stirred at 20° C. for 2 hours and then at 50° C. for 2hours. The solvent was distilled off and the3-methoxy-5-methylpyrazine-2-carboxamide was purified by columnchromatography (eluent: ethyl acetate/methanol 4:1). This gave 5 g of3-methoxy-5-methylpyrazine-2-carboxamide. The yield was 50 percent.Other data concerning the title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 8.10 (s, 1H);

7.84 and 7.56 (2s, broad 2H);

3.93 (s, 3H);

2.46 (s, 3H).

¹³ C-NMR (DMSO-d₆, 400 MHz) δ: 165.5 (s);

156.6 (s);

152.4 (s);

134.5 (s);

134.3 (d);

53.4 (q);

20.7 (q).

(c) Synthesis of 3-methoxy-5-methylpyrazine-2-carboxamide

Under argon, 6 g (60.5 mmol) of 2-amino-2-cyanoacetamide was initiallycharged in 67 g of methanol. 1.67 g (9.3 mmol) of sodium methoxidesolution (30%) was added and the mixture was stirred at 20° C. for 2hours. At 0° C., 11.55 g (64.1 mmol) of methylglyoxal solution (40%) wasadded and the mixture was stirred at 0° C. for 2 hours. The solution wasthen cooled to -20° C. The product precipitated out. After filtrationand drying, 3.56 g of the title product was obtained. The yield was 39percent. The melting point of the title product was 170° C. to 172° C.Other data concerning the title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 8.10 (s, 1H);

7.84 and 7.56 (2s broad, 2H);

3.93 (s, 3H);

2.46 (s, 3H).

¹³ C-NMR (DSMO-d₆, 400 MHz) δ: 165.5 (s);

156.6 (s);

152.4 (s);

134.5 (s);

134.3 (d);

53.4 (q);

20.7 (q).

EXAMPLE 2

(a) Synthesis of 3-methoxy-5-methylpyrazine-2-amine

3.71 g (56.2 mmol) of potassium hydroxide (85%) and 31 g of water wereinitially charged in a flask. At 1° C., 2.16 g (13.5 mmol) of brominewas added dropwise over a period of 10 minutes. This potassiumhypobromite solution was added dropwise at 4° C. to an aqueous solutionof 2.27 g (13.1 mmol) of 3-methoxy-5-methylpyrazine-2-carboxamide in 12g of water. The mixture was stirred at 1° C. for one hour and then at98° C. for 3 hours. The resultant 3-methoxy-5-methylpyrazine-2-amine wasextracted at 20° C. using methylene chloride (2 times 25 ml). Removal ofthe solvent gave 0. 92 g of 3-methoxy-5-methylpyrazine-2-amine. Theyield was 50.4 percent. The melting point of the title product was 75°C. to 76.5° C. The other data concerning the title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 2.20 (s, 3H);

3.87 (s, 3H);

5.90 (s, 2H);

7.33 (s, 1H).

(b) Synthesis of 3-methoxy-5-methylpyrazine-2-amine

1.54 g (23.3 mmol) of potassium hydroxide (85%) and 15 g of water wereinitially charged in a flask. At 1° C., 1.08 g (5.53 mmol) of brominewas added dropwise over a period of 10 minutes. This potassiumhypobromite solution was added dropwise at 4° C. to an aqueous solutionof 1.04 g (5.76 mmol) of 3-methoxy-5-methylpyrazine-2-carboxamide in 6.5g of water. The mixture was stirred at 1° C. for 1 hour and then at 83°C. for 3 hours. The 3-methoxy-5-methylpyrazine-2-amine was extracted at20° C. using methylene chloride (2 times 15 ml). Removal of the solventgave 0.65 g of the title product. The yield was 80 percent. The meltingpoint of the title product was 75° C. to 76.5° C. Other data concerningthe title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 2.20 (s, 3H);

3.87 (s, 3H);

5.90 (s, 2H);

7.33 (s, 1H).

EXAMPLE 3

Synthesis of 3-methoxypyrazine-2-carboxamide

Under argon, 1 g (10.1 mmol) of 2-amino-2-cyanoacetamide was initiallycharged in 10 g of methanol. 0.25 g (1.4 mmol) of sodium methoxidesolution (30%) was added and the mixture was stirred at 20° C. for 2hours. After neutralization with 0.084 g (1.4 mmol) of acetic acid, 2.27g (20 mmol) of glyoxal solution (40%) was added. The mixture was stirredat 20° C. for 2 hours and then at 50° C. for 2 hours. The solvent wasdistilled off. This gave 0.75 g of 3-methyoxypyrazine-2-carboxamide. Theyield was 50 percent. Other data concerning the title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 3.18 (s, 3H);

3.95 (s, 3H);

7.63 (s, 1H);

7.93 (s, 1H);

8.22 (d, 1H, J=1 Hz);

8.37 (d, 1H, J=1 Hz).

EXAMPLE 4

Synthesis of methyl 3-methoxy-5-methylpyrazine-2-carboxylate

Under argon, 5 g (19.3 mmol) of 2-aminomalononitrile-4-toluenesulfonatewas initially charged in 50 g of methanol. 4.09 g (22.7 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred at 2° C.for 2 hours. After neutralization with 0.204 g (3.4 mmol) of aceticacid, 3.6 g (19.9 mmol) of methylglyoxal solution (40%) was added. Themixture was stirred at 40° C. for 2 hours and then, at 20° C., 9.2 g (80mmol) of hydrochloric acid (32%) was added and the mixture was stirredat 20° C. for 6 hours. The solvent was distilled off and the methyl3-methoxy-5-methylpyrazine-2-carboxylate was extracted with methylenechloride. This gave 1 g of methyl3-methoxy-5-methylpyrazine-2-carboxylate. The yield was 27 percent.Other data concerning the title product was:

¹ H-NMR (CDCl₃, 400 MHz) δ: 2.54 (s, 3H);

3.98 (s, 3H);

4.07 (s, 1H);

8.12 (s, 1H).

¹³ C-NMR (CDCl₃, 400 MHz) δ: 21.4 (q);

52.7 (q);

54.2 (q);

129.7 (s);

135.4 (d);

155.4 (s);

158.9 (s);

164.3 (s).

EXAMPLE 5

Synthesis of 3-methoxy-5-methylpyrazine-2-carboxamide

1 g (5.5 mmol) of methyl 3-methoxy-5-methylpyrazine-carboxylate wasinitially charged in 15 ml (198 mmol) of NH₃ (25%) and the mixture wasstirred at 50° C. After concentration, 0.8 g of3-methoxy-5-methylpyrazine-2-carboxamide was obtained. The yield was 86percent. Other data concerning the title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 8.10 (s, 3H);

7.84 and 7.56 (2s broad, 2H);

3.93 (s, 3H);

2.46 (s, 3H).

EXAMPLE 6

Synthesis of 3-methoxy-5-phenylpyrazine-2-carboxamide

Under argon, 2 g (20 mmol) of 2-amino-2-cyanoacetamide was initiallycharged in 15 g of methanol. 0.55 g (3 mmol) of sodium methoxidesolution (30%) was added and the mixture was stirred at 20° C. for 2hours. At 0° C., 3.2 g (21 mmol) of phenylglyoxal was added and themixture was then stirred at 0° C. for 2 hours and concentrated. Theproduct was purified by column chromatography (eluent ethylacetate/methanol 4/1). This gave 3 g of3-methoxy-5-phenylpyrazine-2-carboxamide. The yield was 65 percent.Other data concerning the title product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ: 4.04 (s, 3H);

7.5-8.0 (m, 7H);

8.83 (s, 1H).

¹³ C-NMR (DMSO-d₆, 400 MHz) δ: 53.45;

127;

128.7;

130.24;

131.7;

134.99;

135.90;

149.4;

156.66;

165.3.

MS: 229 (100%)

What is claimed is:
 1. An alkoxypyrazine derivative of the formula:##STR13## in which R¹ denotes alkyl, R³ denotes alkyl or aryl, and R²denotes CONH₂ and COOR⁴, in which R⁴ denotes alkyl.
 2. Thealkoxypyrazine derivative of the formula Ia according to claim 1, whichis selected from the group consistingof:3-methoxy-5-methylpyrazine-2-carboxamide; and3-ethoxy-5-methylpyrazine-2-carboxamide.
 3. The alkoxypyrazinederivative of the formula Ia according to claim 1, which is selectedfrom the group consisting of:methyl3-methoxy-5-methylpyrazine-2-carboxylate; methyl3-ethoxy-5-methylpyrazine-2-carboxylate; ethyl3-methoxy-5-methylpyrazine-2-carboxylate; and ethyl3-ethoxy-5-methylpyrazine-2-carboxylate.
 4. An alkoxypyrazine derivativewhich is 3-methoxy-5-phenylpyrazine-2-carboxamide; and3-ethoxy-5-phenylpyrazine-2-carboxamide.
 5. An alkoxypyrazine derivativeof the formula: ##STR14## in which R¹ and R³ denote alkyl or aryl and R²denotes C(NH)OR⁴, in which R⁴ denotes alkyl.
 6. The alkoxypyrazinederivative of the formula Ia according to claim 5, which is methyl3-methoxy-5-methylpyrazine-2-imidocarboxylate or methyl3-ethoxy-5-methylpyrazine-2-imidocarboxylate.